Protein kinases are a class of enzymes capable of transferring phosphate groups form ATP to substrate proteins. Phosphorylation can alter the interactions between proteins, the activity, the localization or degradation of target proteins. As protein kinases are involved in virtually all biochemical pathways, they are regarded as key regulators and implicated in various diseases when mutated or misregulated.
Dual-specificity tyrosine phosphorylation-regulated kinases (DYRK) are a subfamily of protein kinases comprising several isoforms including DYRK1A and DYRK1B. DYRK1A and DYRK1B are known to interact with numerous cytoskeletal, synaptic and nuclear proteins and are believed to play important roles in cell proliferation and apoptosis induction (Yoshida et al., Biochem Pharmacol., 76(11):1389-94, 2008). DYRK1A and DYRK1B share 85% identity at the amino acid level, though expression and functional characteristics differ (Aranda et al., FASEB 25, 449-462; 2011). While DYRK1A is ubiquitously expressed, DYRK1B was found in a limited number of tissues and organs such as testis and skeletal muscle (Leder et al., Biochem Biophys Res Commun 254, 474-9, 1999; Lee et al., Cancer Res 60, 3631-7, 2000). DYRK1A plays a role in cell proliferation and neural differentiation. Transgenic mice overexpressing DYRK1A show learning and memory disabilities. In Down syndrome patients, the gene encoding DYRK1A is present in three copies. It has been observed that trisomy driven overexpression of DYRK1A is associated with early onset Alzheimer's disease. At the gene level, overexpression of DYRK1A is responsible for the deregulation of more than 200 genes and phosphorylation of numerous proteins, including APP, Tau, presenilin and septin-4 which are key proteins in the pathogenesis of Alzheimer's disease (Ferrer et al., Neurobiol Dis 20, 392-400, 2005; EP 2744797).
Moreover, DYRK1A has been implicated in inflammatory as well as autoimmune diseases due to its inhibiting the differentiation of T helper cells. Many autoimmune and other inflammatory diseases are thought to be caused by T regulatory cells (Treg cells), which are responsible for shutting down inflammation processes once they are no longer needed. It is suggested that increased DYRK1A activity inhibits the differentiation of Treg cells thereby failing to stop inflammatory responses (Khor et al., Elife, 22; 4, 2015). Against this background, it is also notable that Down syndrome patients have hypofunctional Treg cells thereby being prone to an increased risk for autoimmune diseases (Pellegrini et al., Clin Exp Immunol., 169(3):238-43, 2012).
As regards cancer, DYRK1A has been implicated in the resistance of cancer cells to pro-apoptotic stimuli and drives several pathways that lead to increased proliferation, migration as well as a reduction of cell death. By consequence, such cancers typically exhibit very aggressive biological characteristics (Ionescu et al., Mini Rev Med Chem, 12(13):1315-29, 2012).
In contrast to DYRK1A, the gene coding for DYRK1B is located on chromosome 19 (Leder at al., Biochem Biophys Res Commun 254, 474-9, 1999) and is frequently amplified in cancer cells, including pancreatic and ovarian cancer cells (Friedman, J Cell Biochem 102: 274-279, 2007; Deng and Friedman, Genes Cancer, 5(9-10): 337-347, 2014).
DYRK1B has been demonstrated to support the survival of cancer cells (Deng et al., Cancer Res, 66(8):4149-58, 2006; Mercer at al., Cancer Res, 66(10):5143-50, 2006). DYRK1B is overexpressed in approximately 89% of tissue samples of pancreatic ductal adenocarcinomas and 75% of ovarian cancers, as well as in gliomas, leukemias, lung, breast, colon, skin, and other cancers. Levels of DYRK1B are increased 10-fold in some cancer cell populations, especially though not necessarily in quiescent cancer cells, which are known to be comparatively insensitive to anti-cancer therapies, such as chemotherapeutic drugs, targeted drugs, and radiation (Borst, Open Biol 2: 120066, 2012; Komarova and Wodarz, PLoS One 2: e990, 2007). Upon reentry of the cell-cycle, quiescent cancer cells can cause tumor regrowth or recurrence (Ewton et al., Mol Cancer Ther, 10(11):2104-14, 2011). Concerning the underlying mechanism, it was shown that DYRK1B increases expression of antioxidant genes, which results in a decrease in reactive oxygen species and, consequently, an increase in quiescent cell viability (Deng and Friedman, Genes Cancer, 5(9-10): 337-347, 2014). Furthermore, DYRK1B has been shown to play a role in adipogenesis and glucose homeostasis associating its function with metabolic diseases such as the metabolic syndrome (Keramati, N Engl J Med., 370(20): 1909-1919, 2014).
Hence, kinases of the DYRK family are believed to be important targets for the treatment of neurodegenerative, proliferative, inflammatory, autoimmune and metabolic diseases. A feasible approach towards the treatment of said diseases is the use of natural or synthetic kinase inhibitors, several of which have been reported for DYRK1A and DYRK1B.
Regarding natural compounds, the plant-derived polyphenol epigallocatechin gallate (EGCG), the β-carboline alkaloid harmine and its analogues, marine alkaloid leucettamine B and its analogues, and analogues of marine alkaloid meridianin have been identified as DYRK1A inhibitors. Harmine, has been found to inhibit DYRK1B as well. However, EGCG and harmine, and other known DYRK1 inhibitors suffer from lack of selectivity and/or activity thus substantially limiting their value as selective inhibitors. Regarding synthetic compounds, pyridopyrimidine, pyrazolidinedione and benzothiazole or thiazole derivatives have been demonstrated to inhibit DYRK1A. In addition, several small molecules which were originally designed to inhibit other protein kinases, such as purvalanol A, 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT) and 4,5,6,7-tetrabromo-1H-benzotriazole (TBB), were described as somewhat efficient in inhibiting DYRK1A activity. However, the limited selectivity and/or activity of said inhibitors remains a significant downside (Becker and Sippl, FEBS J, 278(2):246-56 2011). Furthermore, WO 2012/098068 relates to pyrazolo pyrimidines as inhibitors for DYRK1A and DYRK1B and treatment of proliferative diseases, including cancer, Down syndrome and early onset Alzheimer's disease. However, 7-azaindole-quinoline structures are not described.
WO 2003/082868 relates to 3,5-substituted 7-azaindole derivatives and their use for inhibition of c-Jun N-terminal kinases. WO 2005/085244 relates to 3,5-substituted azaindole derivatives and their use in the inhibition of c-Jun N-terminal kinases.
In view of the above, there is a need for further compounds which inhibit DYRK1A and/or DYRK1B kinase activity in a potent and/or selective manner in order to be capable of treating diseases linked to abberant expression and/or activity of DYRK1A and/or DYRK1B, and more particularly to increase in expression and/or activity of DYRK1A and/or DYRK1B. In particular, there is a need for compounds which are suitable for the treatment of diseases such as neurodegenerative, proliferative, inflammatory, autoimmune and metabolic diseases.